tbuckley/cabot-search huggingface dataset:
Association of 27-gene IO score with outcome in a phase Ib trial of pembrolizumab (pembro) plus chemotherapy (CT) in metastatic triple-negative breast cancer (mTNBC).
Authors: David B. Page, Krystle Louise Collins, Venkatesh Rajamanickam, Nicole Moxon, Staci L. Mellinger, Alison Katherine Conlin, Robert Seitz, Kim McGregor, Tyler J. Nielsen, Heather L. McArthur
Journal: Journal of Clinical Oncology (2022)

1082 Background: The IO score is a is a 27-gene signature developed to classify the tumor immune microenvironment derived from the 101-gene TNBCtype genomic classifications. The IO score predicts clinical outcome following immune checkpoint inhibitor therapy in NSCLC and bladder cancer, and recently was shown to predict benefit by pCR of atezolizumab plus CT over neoadjuvant CT alone in early stage TNBC (NeoTRIPaPDL1 trial). The IO score has not yet been evaluated in mTNBC or with pembro in breast cancer. Methods: We report preliminary associations of IO score with response from a phase Ib trial (NCT02734290). mTNBC subjects received 1st/2nd line pembro (200mg IV q3wk) plus investigator’s choice paclitaxel (80mg/m2 IV q1wk, n = 15) or capecitabine (2000mg PO BID x 7d, q2wk, n = 14). Baseline (n = 23) and on-treatment (at wk 6, n = 10) biopsies were analyzed for IO score and genomic subtype by RNA exome sequencing. Objective response rate (ORR, partial or complete response, 12 weeks) and survival was determined among response-evaluable subjects (n= 21). Tumor PD-L1 was assessed by IHC (combined positive score, CPS &gt; 10%). The IO signature was analyzed as a binary classifier (IO+/IO-) and as a continuous variable (IO score). Results: 39% of evaluable subjects were IO+ (n =9/23). IO+ was associated with improved clinical outcome, including ORR (IO+ 43%, IO- 29%), median progression free survival (mPFS, IO+ 138d, IO- 79d), and median overall survival (mOS, IO+ 687d, IO- 305d). IO+/IO- classification and IO scores were stable across serial biopsies (Cohen’s kappa = 0.74, r = 0.84). IO score was not strongly correlated with PD-L1 CPS (r = 0.27) or sTILs (r =.09). PD-L1-/IO+ tumors constituted 31% (n = 5/16) of PD-L1- cases and exhibited favorable outcome (ORR 40%, mPFS 162d, mOS 556d). IO score and ORR varied across TNBCtype classifications (BL1 subtype: 50% ORR, 66% IO+; BL2 subtype: 0% ORR, 66% IO+; LAR subtype: 50% ORR, 0% IO+, MSL subtype: 33% ORR, 60% IO+). Conclusions: IO score is associated with favorable outcome following pembro + CT, and may identify PD-L1-negative cases that respond to pembro + CT. Further investigation in larger datasets is warranted to ascertain the clinical utility of IO score in this setting. Funding: Drug support and funding provided by Merck Sharpe &amp; Dohme as part of the Merck Investigator Studies Program. Clinical trial information: NCT02734290.
Prognostic role of the stromal tumor-infiltrating lymphocytes (TILs) in women with early ER+/HER2+ breast cancer (BC) in whom adjuvant chemotherapy (ChT) was omitted.
Authors: Valentina Jeric Horvat, Damjan Manevski, Barbara Gazic, Primoz Drev, Erika Matos, Domen Ribnikar, Bostjan Seruga
Journal: Journal of Clinical Oncology (2022)

e12526 Background: Adjuvant systemic therapy in women with early ER+/HER2+ BC usually includes ChT, trastuzumab (T) and endocrine therapy (ET). High level of TILs is associated with better outcome in HER2+ disease. Here we explore the outcome and prognostic role of TILs in women with early ER+/HER2+ BC in whom ChT was omitted. Methods: Women with ER+ (IHC ≥ 1%) and HER2+ (IHC3+ and/or FISH ratio ≥ 2.0) early BC who underwent surgery between years 2006 and 2016 at the Institute of Oncology Ljubljana and did not receive adjuvant ChT were eligible for this study. Hematoxilin and eosin slides of primary tumors were retrieved and evaluated for the percentage of stromal TILs. Distant disease-free survival (DDFS) was estimated by the Kaplan-Meier method. The association between DDFS and TILs level was explored in the Cox proportional hazard model. Relative survival was used for estimating the probability of dying due to the breast cancer or other causes. Results: During the 10-year period 86 (29.4%) out of 292 women with early ER+/HER2+ BC who underwent surgery did not receive adjuvant ChT. ChT was omitted due to the stage I disease (n=30), comorbidities (n=25), older age (n=19), refusal of treatment (n=9) and other causes (n=3). Five (5.8%) and 81 (94.1%) women received T and ET, respectively. Their median age was 65.8 yrs (IQR 55.7, 75.6 yrs) and 45 (52.3%) had stage I disease. There were 53 (61.6%), 24 (27.9%) and 9 (10.4%) women with low (&lt;10%), intermediate (≤10% to &lt;40%) and high (≥ 40%) level of TILs, respectively. After median follow-up of 10 years 28 events (distant recurrence or death) occurred. The 10-year DDFS for those who did not receive ChT due to the stage I disease, comorbidities and older age was 91% (95% CI, 0.79 to 1.00), 38% (95% CI, 0.18 to 0.75]) and 26% (95% CI, 0.10 to 0.66) (p˂0.0001), respectively. After excluding women with stage I disease the estimated probability of dying due to the breast cancer and due to other causes was 26.7% and 26.5%, respectively. Overall, for every 10% increase in TILs the risk of distant recurrence or death was reduced for 18% (HR=0.82; 95% CI, 0.64 to 1.05) (p=0.11). In the multivariable Cox model, higher TILs level was a significant predictor of better DDFS (HR 0.75; 95% CI, 0.57 to 0.98) (p=0.041) (Table). Conclusions: Women with stage I ER+/HER2+ BC who do not receive adjuvant ChT and T but do receive adjuvant ET may still have a very good outcome. In contrast, survival of women who do not receive adjuvant ChT and T for other reasons is poor; however, only a half of those deaths are related to BC. TIL is a favourable prognostic biomarker which might be helpful when de-escalation of systemic therapy in women with ER+/HER2+ BC is considered.[Table: see text]
Significance of position of vesico-urethral anastomosis together with postoperative membranous urethral length for short term continence recovery following robot-assisted laparoscopic radical prostatectomy
Authors: Y. Nakanishi, S. Matsumoto, N. Okubo, K. Tanabe, M. Kataoka, S. Yajima, H. Masuda
Journal: European Urology (2022)
EPEN-28. Oncogenic dependency of pediatric ependymomas on extracellular vesicle pathways
Authors: Kendra K Maass, Mieke M Roosen, Torsten Mueller, Daniel Senfter, Julia Benzel, Tatjana Wedig, Mathias Kalxsdorf, Jeroen Krijgsveld, Stefan M Pfister, Kristian W Pajtler
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION: The majority of pediatric ependymoma (EPN) comprise either supratentorial EPN characterized by ZFTA-fusions (ST-EPN-ZFTA) or posterior fossa group A EPN (PF-EPN-A), for both of which only limited therapeutic options are available. Because pediatric EPNs have a relatively low mutational burden, identification and characterization of tumor-associated pathways and molecular processes are of critical importance to reveal potential therapeutic targets. Data from previous transcriptional studies and a cross-species in vivo screen implied aberrant vesicular pathways in ST-EPN-ZFTA, prompting further investigation of their putative role in EPN pathogenesis. METHODS: We investigated EPN group-specific differences in extracellular vesicle (EV) biogenesis pathways in human EPN transcriptome and proteome datasets. In addition, we characterized isolated EPN EVs by mass spectrometry. EPN-specific EV cargo was further investigated by immunofluorescence staining and western blotting. This enhanced understanding of EPN vesicular signaling allowed for a pre-selection of inhibitors targeting specific EV biogenesis pathways. In vitro proliferation and invasion assays as well as in vivo treatment studies were performed on EPN model systems. RESULTS: Integration of multi-omic data from both EPN tissues and EPN-EV-associated proteome led to the identification of ST-EPN-ZFTA-specific EV populations. We could spatially map specific EV markers to the perivascular niche that primarily harbors undifferentiated ST-EPN-ZFTA cell populations. Targeting EV biogenesis pathways by inhibiting factors of the lipid metabolism reduced the abundance of released EVs resulting in altered growth behavior and decreased invasion of tumor cells in vitro. In vivo validation of EV release inhibitors in an orthotopic ST-EPN-ZFTA PDX model significantly reduced tumor growth and increased survival. OUTLOOK: In summary, we have leveraged ST-EPN-ZFTA-specific EV pathways as a potential therapeutic vulnerability. Further mechanistic investigations on EPN EV biogenesis, release, or uptake are expected to improve our understanding of the cross-talk between tumor cells and cells of the microenvironment and may lead to potential new therapeutic avenues.
An examination of translated content on NCI-designated cancer websites with a focus on breast and colorectal cancer.
Authors: Minira Aslanova, Megan C Buckley, Gres Karim
Journal: Journal of Clinical Oncology (2022)

6576 Background: One unforeseen implication of the pandemic has been a greater reliance on health information sharing via the Internet. This is complicated by the fact that many healthcare websites and online resources fail to consider Limited English Proficiency (LEP) when designing websites that relay essential health information. We aimed to quantify the extent to which NCI-Designated Cancer Center websites provide language accessibility. Methods: Over the course of 2021, we performed a cross-sectional review of translation services and available languages on NCI-Designated Cancer Center websites. This study was particularly focused on both breast cancer and colorectal cancer portions of these websites. The primary out-comes were as follows: option of translated content, presence of more than one language, and method by which the translation was performed (written text vs. Google scholar). We referred to the 2015 US language map for the percentage of LEP by state. Results: Of the 71 NCI-Designated Cancer Centers, 56 (78.9%) were without translation, and 15 (21.1%) used either manual translation or displayed a link for Google translate. Of the 15 centers who offered translated content on their website, 15/15 (100%) had more than one language available in the drop down list. Spanish (100%) was the most common language available. In terms of Limited English Proficiency, 25 of 71 (35.21%) NCI-Designated Cancer Centers were located in states where greater than 10% of the population is defined as having LEP, and yet, only 5 of these centers (20.0%) had languages other than English featured. We observed no significant relationship between the state LEP percentile and the number of NCI-Designated Cancer Centers offering website translation services within that state. Additionally, no appreciable differences in language availability were observed between breast cancer and colorectal cancer. Conclusions: Overall, only a fraction of NCI-Designated Cancer Centers actually translate the content of their websites. In New York for example, despite having the highest percentage of residents with LEP at 19.345%, only one of ten NCI-Designated Cancer Centers within the state had a website with language translation. We believe this represents a missed opportunity as language inaccessibility may contribute to delays in care for non-English speaking patients, particularly in a post pandemic world, further exacerbating health care disparities among patient populations.
Cardiac progenitor cell-derived extracellular vesicles skew human macrophages towards a pro-inflammatory phenotype
Authors: AM Carmo Viola, P Vader, SCA De Jager, JPG Sluijter
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): This research is support by the European Research Council (ERC) consolidator grant EVICARE (ERC-2016-COG-725229). Background Repair of damaged heart tissue upon myocardial infarction remains a major challenge. Transplantation of cardiac progenitor cells (CPCs) has been studied as a potential regenerative therapy, but recent studies have shown that the cardioprotective effect of CPCs is mediated by the release of extracellular vesicles (EVs). The benefits of CPC-derived EVs have mostly been associated with stimulation of angiogenesis and inhibition of cell death. Although macrophages have been suggested to be key for cardiac repair, the effect of CPC-EVs on macrophage polarization is poorly explored. Purpose Here, we hypothesized that CPC-derived EVs can modulate the inflammatory response after myocardial infarction by interacting with macrophages. Methods EVs were isolated from serum-starved CPCs by ultrafiltration followed by size exclusion chromatography. Human monocytes were isolated from the blood of healthy donors and differentiated into macrophages with M-CSF. Macrophages were subsequently stimulated with LPS + IFNy or with IL4 in order to induce an inflammatory M1 and reparative M2 phenotype, respectively. A third group of macrophages were cultured in media without LPS, IFNy or IL4 to resemble naive M0 macrophages. The obtained macrophages were exposed to CPC-EVs and analyzed by flow cytometry, bulk RNA sequencing and confocal microscopy to assess macrophage phenotype changes. Gene candidates were selected based on the p-value and fold-change, and validated by RT-PCR. Small molecule inhibitors were used to further investigate the mechanism by which CPC-EVs are taken up by macrophages and the pathways involved in macrophage response. Results Stimulation of macrophages with CPC-EVs enhanced the expression of the pro-inflammatory marker CD80, while slightly decreasing the anti-inflammatory marker CD206, in M0 and M2 macrophages. CPC-EV-stimulated macrophages also adopted a morphology that reflects the inflammatory macrophage. In line with these findings, bulk RNA sequencing on M0 and M2 polarized macrophages revealed upregulation of genes involved in inflammatory response, including cytokine and both type I and II interferon signaling. EV exposure did not significantly affect gene expression in M1 polarized macrophages. Ongoing investigations will provide in-depth insight into the mechanism by which CPC-EVs induce this response in macrophages. Conclusion Our data suggests that CPC-EVs are able to induce macrophage polarization towards an inflammatory phenotype, which might have implications for CPC-EV treatment after myocardial infarction. This underlines an urgent need to understand the molecular mechanisms underlying the immunomodulatory effect of CPC-derived EVs before moving into a clinical setting.
circRNA422 enhanced osteogenic differentiation of bone marrow mesenchymal stem cells during early osseointegration through the SP7/LRP5 axis
Authors: Ke Yu, Zhiwei Jiang, Xiaoyan Miao, Zhou Yu, Xue Du, Kaichen Lai, Ying Wang, Guoli Yang
Journal: Molecular Therapy (2022)

Circular RNAs (circRNAs) play an important role in biological activities, especially in regulating osteogenic differentiation of stem cells. However, no studies have reported the role of circRNAs in early osseointegration. Here we identified a new circRNA, circRNA422, from rat bone marrow mesenchymal stem cells (BMSCs) cultured on sandblasted, large-grit, acid-etched titanium surfaces. The results showed that circRNA422 significantly enhanced osteogenic differentiation of BMSCs with increased expression levels of alkaline phosphatase, the SP7 transcription factor (SP7/osterix), and lipoprotein receptor-related protein 5 (LRP5). Silencing of circRNA422 had opposite effects. There were two SP7 binding sites on the LRP5 promoter, indicating a direct regulatory relationship between SP7 and LRP5. circRNA422 could regulate early osseointegration in in vivo experiments. These findings revealed an important function of circRNA422 during early osseointegration. Therefore, circRNA422 may be a potential therapeutic target for enhancing implant osseointegration.
Inhibition of cancer stem cells with TACH101, a first-in-class inhibitor of KDM4 histone lysine demethylase.
Authors: Frank Perabo, Chandtip Chandhasin, Van Dang, Joselyn Del Rosario, Young K Chen, Ellen Filvaroff, Jeffrey Stafford, Stephen Quake, Michael F. Clarke
Journal: Journal of Clinical Oncology (2022)

e15105 Background: Cancer stem cells (CSCs) are believed to be responsible for both therapy resistance and metastasis. Until now, these resistant CSCs have not been well-characterized, and potential treatments targeting these cells have yet to be identified. Epigenetic modifiers, such as KDM4 histone demethylase, have been shown to play an important role in CSC renewal and maintenance. TACH101 is a novel, first-in-class pan inhibitor of KDM4 that has promising pre-clinical and pharmacologic properties as a possible cancer therapeutic. Methods: Effects of TACH101 on CSC population were evaluated in the colorectal cancer SU60 xenograft model. Mice engrafted with SU60 cells were treated with TACH101 or vehicle. The day after the last dose, tumors from each group were dissociated into single cells and used to perform (1) flow cytometry analysis of the tumorigenic cell population using markers CD44 and EpCAM, (2) single cell gene expression analysis using quantitative reverse transcription polymerase chain reaction (RT-qPCR), and (3) functional tumorigenicity assays (limiting dilution assays). Results: TACH101 administration reduced SU60 tumor growth by 62% compared to vehicle-treated mice (p &lt; 0.0005). Flow cytometry analysis of SU60 tumor cells showed the proportion of cells with cancer stem cell features (CD44 High EpCAM + ) was 2.5-fold lower in TACH101-treated mice as compared to vehicle-treated animals. Single cell gene expression analysis followed by hierarchical clustering based on expression of immature and mature cell markers showed that TACH101-treated tumors had a significant reduction in the proportion of progenitor-like cells (p = 0.01) and an increase in number of both intermediate-like and differentiated-like cells although the increase was not significant (p = 0.07). In limiting dilution assay experiments, result showed that tumors were bigger/grew faster in animals receiving tumor cells derived from vehicle-treated animals compared to TACH101-treated animals. Furthermore, TACH101 was shown to reduce the number of tumor-initiating cancer stem cells by 4.4-fold. Further evaluation of TACH101 across additional xenograft models including esophageal, gastric, breast, and lymphoma showed tumor growth inhibition of up to 100%. TACH101 demonstrated favorable cell permeability, good oral bioavailability, and high metabolic stability. Toxicity studies in rats and dogs identified potential target tissues and provided safety guidance for the use of TACH101 in human trials. Conclusions: TACH101 inhibited proliferation of and tumor initiation by CSCs. As therapy resistance and metastatic dissemination are grave consequences of CSC activity, TACH101 provides a novel approach to eradicating this population and shows broad applicability as a potential therapeutic agent. Preparations to advance TACH101 into clinical trials are underway.
PATH-13. Methylation analysis in the diagnosis of pediatric CNS tumors; a single center experience
Authors: Maria Filippidou, Ilona Binenbaum, Stavros Glentis, Kleoniki Roka, Antonia Vlachou, Georgia Avgerinou, Kalliopi Stefanaki, Florian Selt, Till Milde, Felix Sahm, Olaf Witt, David T Jones, Stefan M Pfister, Antonis Kattamis
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Tumors of Central Nervous System (CNS) comprise major cause of cancer-related morbidity and mortality during childhood. Recent advances in genome and epigenome research allow for molecular classification of CNS tumors, treatment stratification and therapeutic target identification. In many countries, including Greece, this integrated diagnosis is not possible, yet, in a routine setting due to financial and infrastructural reasons. DESIGN/METHODS: We analyzed the results from the methylation profiling performed on tumor samples from newly diagnosed and selected retrospective patients followed in our unit. Analyses were performed through the PTT2.0 and MNP2.0 Studies, as part of a collaboration project between ACCC (Athens Cancer Comprehensive Center) and DKFZ (German Cancer Research Center). RESULTS: Methylation arrays from 50 patients (mean age: 8years, range: 0-17years) have been analyzed. High calibrated score (&amp;gt;0.9) was achieved in 38 patients (76%) and in 33 (86%) of these, the histological diagnosis matched the methylation class. The remaining 5 cases, diagnosed by the local pathologist as ganglioneuroma, primitive neuroectodermal tumor, anaplastic astrocytoma, pineoblastoma and oligodendroglioma, were classified according to the methylation profiling as dermatofibrosarcoma protuberans, medulloblastoma group 3, high-grade glioma H3.3G34mutant, high-grade neuroepithelial tumor with BCOR alteration and glioneuronal tumor, respectively. Only four cases had no match in the classifier, while seven cases received low score (0.5-0.8). In 6 out of the 7 cases with low score, the diagnosis was confirmed with the use either of the copy-number profile inferred from the methylation array or by additional testing for gene fusions and mutations. In 25 medulloblastomas, methylation profiling provided molecular classification, according to the 2021 WHO Classification. CONCLUSIONS: Our experience on the first 50 cases suggests that methylation array needs to be considered as an integral part of the diagnostic process of pediatric patients with CNS tumors and highlights the importance of international collaboration programs in pediatric neuro-oncology.
High-risk non-16 human papillomavirus genotypes in head and neck squamous cell carcinoma.
Authors: Michael Wotman, Rocco Ferrandino, Brandon Gold, Nicole Albstein, Naomi Alpert, Jacqueline Junn, William Westra, Marshall R. Posner
Journal: Journal of Clinical Oncology (2022)

e18052 Background: Oropharyngeal cancer patients with Human Papillomavirus (HPV)-associated disease have more favorable outcomes. HPV16 is the primary genotype in this population. Our knowledge of the impact of high-risk non-16 HPV (HRN16) subtypes on survival is limited. The objective of this study is to investigate the incidence, demographics, and survival outcomes of HRN16 genotypes in patients with HPV-positive head and neck squamous cell carcinoma (HNSCC). Methods: This is a retrospective chart review of patients diagnosed with HPV+ HNSCC from 2012-2021 at the Mount Sinai Health System. Genotyping was performed with polymerase chain reaction (PCR). Demographic, clinical and tumor data was extracted from electronic medical records.The primary outcomes are overall survival (OS) and event-free survival (EFS) for patients with non-metastatic disease at presentation, treated with curative-intent, with &gt; 6 months follow-up.Survival analysis was performed by Kaplan-Meier method. Results: 733 patients had HPV+ HNSCC, and 109 (14.9%) are HRN16 subtypes. Mean age at diagnosis is 62.4 years. Most individuals are non-Hispanic white males, non-active smokers, social drinkers, and have good performance status (Table). A majority has non-metastatic oropharyngeal cancer treated with standard of care (SOC) definitive therapy. The predominate genotypes are HPV35 (39.4%, n = 41), HPV33 (27.9%, n = 29), and HPV18 (14.4%, n = 15). Survival analysis demonstrated no significant differences in OS (log-rank p = 0.90) and EFS (log-rank p = 0.19) among the different HRN16 subtypes. There was a trend for better EFS for HPV35. Conclusions: HRN16 genotype may not meaningfully impact patient outcomes in HNSCC. Larger multivariate analyses may identify specific site and genotype differences in survival comparedwith HPV16-assoicated disease and indicate if patients with selected HRN16 subtypes are candidates for treatment de-escalation.[Table: see text]
Diagnostic performance of Fusion (US/MRI guided) prostate Biopsy: Comparison of elastic transrectal versus rigid transrectal versus rigid transperineal fusion system
Authors: M. Ferriero, C. Fiori, R. Mastroianni, L. Misuraca, S. Decillis, E. Checcucci, F. Porpiglia, A. Bove, G. Tuderti, U. Anceschi, A. Brassetti, S. Guaglianone, M. Gallucci, G. Simone
Journal: European Urology (2022)